Chemical mixing systems often include an agitator mechanically connected to a drive shaft or a post that is lowered into a fluid through an opening in the top of a vessel, and then rotated using external motors. In closed systems, agitators are often connected to external motors via hydraulically sealed drive shafts. However, because of potential contamination of the fluid in the vessel and potential leaking, these types of agitator are generally not practical for mixers and bioreactors used in manufacturing of pharmaceuticals or biological materials.
Magnetic coupling of an agitator inside the vessel to a drive system or motor external to the mixer or bioreactor can eliminate contamination issues, allow for a completely enclosed system, and prevent leakage. Because there is no need to have a drive shaft penetrate the bag support structure wall to mechanically spin the agitator, magnetically coupled systems can eliminate the need for having seals between the drive shaft and the vessel. Most magnetic agitator systems include a rotating magnetic drive head outside of the vessel and a rotating magnetic agitator (also referred to in this context as the “impeller”) within the vessel. The movement of the magnetic drive head enables torque transfer and thus rotation of the magnetic agitator allowing the agitator to mix a substance within the vessel.
Increasingly, in the biopharmaceutical industry, single use or disposable containers are used. Such containers can be flexible or collapsible plastic bags that are supported by an outer rigid structure such as a stainless steel shell. Use of sterilized disposable bags eliminates time-consuming step of cleaning of the vessel and reduces the chance of contamination. Combining the single use or disposable bags with the magnetic agitator system establishes a sterile environment that is especially important for biopharmaceutical manufacturing.
Magnetic agitator systems currently include particular components to both retain the magnetic agitating element in a certain position within the flexible bag during mixing, and also to maintain coupling and proper alignment between the magnetic agitator and the external magnetic drive head or system. Examples of such components include post or cup-like “receiver” structures that are formed as part of the disposable container, typically as part of a rigid bottom or base of a disposable bag. Such receiver structures added to the expense of container manufacturing—and introduce regions of possible vessel failure if the spinning agitator repeatedly comes in contact with a portion of the receiver structure.
Moreover, the fusion of a thick rigid bottom segment to a container bag also complicates the placement of other process control elements. For example, bioreactor systems typically utilize spargers for introducing a controlled amount of a specific gas or combination of gases into the bioreactor. A sparger outputs small gas bubbles into a liquid in order to agitate and/or dissolve the gas into the liquid. The delivery of gas via spargers helps in mixing a substance, maintaining a homogenous environment throughout the vessel, and is sometimes essential for growing cells in a bioreactor. Ideally, the spargers and the agitator are in close proximity to ensure optimal distribution of the gases throughout the container.
Another problem with magnetic agitator systems lies in how the impeller and driver magnets are coupled together. Two different orientations of the impeller magnets and external driver magnets are commonly used. The two orientations are axial and radial. “Axial orientation” generally means that the direction of the magnetic coupling between the internal and external rotating components is parallel to the axis around which the internal and external components are rotating. The terms “radial” and “Radial orientation” mean that the direction of the magnetic coupling between the internal and external rotating components is at an angle that is not parallel to axis of rotation, e.g., perpendicular to the axis around which the internal and external components are rotating or some intermediate angle greater than 0 degrees and less than 90 degrees relative to the axis of rotation.
In an axially coupled magnetic coupling system the direction of the coupling and de-coupling force is parallel to the direction of the magnetic coupling force. If the nonlinear attractive force between the internal and the external system components during coupling cannot be adequately controlled, the internal and external components can forcefully slam together, damaging the components. Conversely, the force required to separate the internal and external components could damage the components by overstressing the components during de-coupling as the components are pulled apart. This is especially true for the coupling components of a disposable system wherein at least some of the components might be constructed from plastic.
In a radially coupled magnetic coupling system, the nonlinear attractive forces between the internal and external components must also be overcome in a controlled manner when the components approach one other during coupling and as they recede from one other during de-coupling. In the case of a radially coupled system, the forces during coupling and de-coupling would result in what could be called a shearing force; that is, the direction of the force would be perpendicular to the magnetic coupling. If the nonlinear attractive force between the internal and the external system components during coupling cannot be adequately controlled the internal and external components can forcefully slam together on one side of the system, resulting in non-alignment of the coupling components and damaging the components. Conversely, during de-coupling when the internal and external components separate, the components could again slam together in a sideways motion and this could damage the components. Again, this is especially true for the coupling components of a disposable system wherein at least some of the components are plastic materials.
In the worst cases, misalignment of the driver and impeller magnets can lead to complete decoupling and the ejection of the agitator into the fluid volume of the container. Unless the agitator can be re-coupled to the drive mechanism, no further mixing can be accomplished and the batch may be compromised in an attempt to reseat the impeller or, failing successful re-coupling, the entire batch being processed must be discarded. The possibility of decoupling increases with the height of the agitator. In large batch containers, it can be desirable to have the agitator to have an axial shaft that extends for a substantial portion, if not the entire height, of the container and carries several separate sets of vanes, for example, to mix the top, middle and bottom of the fluid column in the container simultaneously. Because the center of gravity for such extended length agitators is at a distance from the impeller hub, misalignment can quickly lead to wobbling and, ultimately, detachment especially at high rotational speeds.
A variety of vessels, devices, components and unit operations for manipulating liquids and/or for carrying out biochemical and/or biological processes are available. Increasingly, single-use or disposable bioreactor bags and single-use mixer bags are used as such vessels. For instance, biological materials (e.g., animal and plant cells) including, for example, mammalian, plant or insect cells and microbial cultures can be processed using bioreactors that include single-use processing bags. Manufacturing of complex biological products such as proteins, monoclonal antibodies, etc.) requires, in many instances, multiple processing steps ranging from fermentation or cell culture (bacteria, yeast, insect, fungi, etc.), to primary recovery and purification. Conventional bioreactor-based manufacturing of biological products generally utilizes batch, or fed-batch processing, or continuous or perfusion mode processing with subsequent off-line laboratory analysis conducted on representative samples collected from various points of the process to ensure quality.
In order to obtain timely information regarding changing conditions within a bioreactor during its operation, the use of sensor technology has been employed. There are recognized difficulties in attaching a sensor to the inside of a flexible-walled bioreactor or flexible tubing. Further, optical, electrical, and pH sensors, for example, positioned inside a flexible bag or tubing require an attachment means that allows for a clear signal to be communicated to or from external analytical instrumentation. There is an ongoing need for an improved disposable sensor assembly and a method for integrating a disposable sensor in flexible disposable bioreactor bags and in downstream tubing.
An improved device and method for integrating a disposable sensor in a flexible bioreactor bag or tubing would also be beneficial for use in bioreactor-based manufacturing systems that include in-line sensing in order to provide real-time data.
Further, there is a need for better disposable bioreactor systems that address one or more of the aforementioned problems. There is a further need for simpler, less expensive, more efficient and/or more robust, magnetic agitation mixer systems for biopharmaceutical manufacturing.